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WO2004112769A1 - Utilisation de derives de bicyclo[2.2.1]heptane pour la preparation de compositions pharmaceutiques neuroprotectrices - Google Patents

Utilisation de derives de bicyclo[2.2.1]heptane pour la preparation de compositions pharmaceutiques neuroprotectrices Download PDF

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Publication number
WO2004112769A1
WO2004112769A1 PCT/HU2004/000062 HU2004000062W WO2004112769A1 WO 2004112769 A1 WO2004112769 A1 WO 2004112769A1 HU 2004000062 W HU2004000062 W HU 2004000062W WO 2004112769 A1 WO2004112769 A1 WO 2004112769A1
Authority
WO
WIPO (PCT)
Prior art keywords
bicyclo
pharmaceutically acceptable
trimethyl
general formula
heptane
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/HU2004/000062
Other languages
English (en)
Inventor
István Gacsályi
Gábor Gigler
László Gábor HÁRSIN
György Lévay
Krisztina MÓRICZ
Annamária SIMÓ
Gábor SZÉNÁSI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MXPA05014127A priority Critical patent/MXPA05014127A/es
Priority to HR20060023A priority patent/HRP20060023A2/xx
Priority to US10/562,393 priority patent/US20060258750A1/en
Priority to EA200600022A priority patent/EA010868B1/ru
Priority to JP2006516495A priority patent/JP2007516165A/ja
Priority to CA002529254A priority patent/CA2529254A1/fr
Priority to SK5008-2006A priority patent/SK50082006A3/sk
Priority to YUP-2005/0954A priority patent/RS20050954A/sr
Priority to BRPI0411772-7A priority patent/BRPI0411772A/pt
Application filed by Egyt Gyogyszervegyeszeti Gyar, Egis Pharmaceuticals PLC filed Critical Egyt Gyogyszervegyeszeti Gyar
Priority to AU2004248982A priority patent/AU2004248982A1/en
Priority to UAA200600574A priority patent/UA81052C2/uk
Priority to EP04743721A priority patent/EP1660063A1/fr
Publication of WO2004112769A1 publication Critical patent/WO2004112769A1/fr
Priority to IL172408A priority patent/IL172408A0/en
Anticipated expiration legal-status Critical
Priority to IS8239A priority patent/IS8239A/is
Priority to NO20060277A priority patent/NO20060277L/no
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a new therapeutical use of bicyclo[2.2.1]he ⁇ tane derivatives. More particularly the present invention is concerned with the use of bicyclo[2.2.1]heptane derivatives for the preparation of pharmaceutical compositions having neuroprotective effect.
  • Deramciclane was ineffective in the elevated plus maze test, but it antagonized anxiety caused by CCK in this test [Gacs ⁇ lyi et. al, Receptor binding profile and anxiolytic activity of deramciclane (EGIS-3886) in animal models, Drug Dev. Res. 40: p.338-348, (1997)]. Besides these anxiolytic effects, deramciclane produced antidepressant activity at 1 and 10 mg/kg ip. doses in the learned helplessness test, which is a known animal model of depression [Grial et al, Biol. Psychiatry, 23, 237-242 (1988)] .
  • deramciclane Based on its receptor profile, deramciclane binds primarily to central 5-HT 2C and 5-HT 2A receptors. Anxiolytic and antidepressant effects of deramciclane can be explained by its affinity for these 5-HT receptors.
  • R stands for hydrogen or hydroxy; R 1 stands for hydrogen or alkyl; and R 2 stands for alkyl) and pharmaceutically acceptable acid addition salts for the preparation of pharmaceutical compositions having neuroprotective effect.
  • the present invention is based on the recognition that compounds of general Formula I produce protection against neuronal injury induced by global cerebral ischemia and consequential pathological changes in behavioural parameters (spontaneous motility). This effect is independent of its known mode of action and of its anxiolytic and stress-reducing effects since ritanserin, a 5-HT 2 A /2C antagonist, i.e. a compound with comparable mode of action to deramciclane, did not show neuroprotective activity in a similar ischemia model (Piera, M. J., et. al, Lack of efficacy of5-HT2A receptor antagonists to reduce brain damage after 3 minutes of transient global cerebral ischaemia in gerbils, Fundam. Clin. Pharmacol,9: p.
  • lower alkyl relates to straight or branched chain saturated aliphatic hydrocarbon group containing 1-4 carbon atom, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl etc.
  • salts relates to salts formed with pharmaceutically acceptable non- toxical inorganic or organic acids.
  • pharmaceutically acceptable non- toxical inorganic or organic acids e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, formic acid, lactic acid, tartaric acid, maleic acid, malic acid, amygdalic acid, fumaric acid, benzenesulfonic acid, p-toluene sulfonic acid etc.
  • Salts formed with fumaric acid are particularly preferable.
  • a preferable embodiment of our invention is the utilization of compounds of general Formula I and their acid addition salts for the preparation of pharmaceutical compositions suitable for the reduction of the consequences of acute ischemic or traumatic brain and spinal damage, especially the various types of stroke or cerebral vasospasm, severe brain vessel occlusion, neuronal loss and its functional consequences in the case of head and spinal injuries caused by accidents.
  • a further preferable embodiment of our invention is the utilization of compounds of general Formula I or of their acid addition salts for the preparation of pharmaceutical compositions suitable for the treatment of neurodegenerative disorders.
  • a further preferable embodiment our invention is the utilization of compounds of general Formula I or acid addition salts thereof for the preparation of pharmaceutical compositions suitable for the treatment of motoneuron disease (ALS), sclerosis multiplex or Creutzfeld- akob disease.
  • ALS motoneuron disease
  • sclerosis multiplex or Creutzfeld- akob disease.
  • a further preferable embodiment of our invention is the utilization of compounds of general Formula I or their acid addition salts for the preparation of pharmaceutical compositions suitable for the prevention of stroke; preventive treatment can be started after the event of first stroke.
  • the neuroprotective dose of the compounds of the general Formula I can be varied between broad ranges and depends on various factors e.g. the activity of the given active ingredient, the body weight, age and condition of the patient to be treated, the seriousness of the treated disease, the form of administration is always determined by the physician.
  • the daily neuroprotective dose is preferably between about 0.1 mg/kg and 150 mg/kg, particularly between about 1 mg/kg and about 150 mg/kg, particularly advantageously between about 10 mg/kg and about 150 mg/kg.
  • (lR,2S,4R)-(-)-2-(2-dimethylaminoethoxy)-2-phenyl- l,7,7-trimethyl-bicyclo[2.2.1]heptane of the Formula II or the pharmaceutically acceptable acid addition salts thereof, particularly (lR,2S,4R)-(-)-2-(2-dimethylaminoethoxy)-2- phenyl-l,7,7-trimethyl-bicyclo[2.2.1]heptane-fumarate can be used for the preparation of neuroprotective pharmaceutical compositions.
  • neuroprotective pharmaceutical compositions comprising as active ingredient a compound of the general Formula I (wherein R , R and R are as stated above) or a pharmaceutically acceptable acid addition salt thereof in admixture with pharmaceutically acceptable solid or liquid pharmaceutical carriers and/or auxiliary agents.
  • compositions of the present invention can be prepared by known methods of the pharmaceutical industry. Thus one may proceed by admixing a compound of the general Formula I or a pharmaceutically acceptable acid addition salt thereof with inert solid or liquid pharmaceutical carriers and/or auxiliary agents and bringing the mixture into galenic form.
  • the neuroprotective pharmaceutical compositions according to the present invention can be administered orally (tablets, coated tablets, hard or soft gelatine capsules, solutions, suspensions etc.), parenterally (e.g. subcutaneous, intramuscular, intravenous injections), rectally (e.g. suppositories) or nasally (e.g. aerosols).
  • the active ingredient can be delivered promptly from the pharmaceutical compositions in which case the duration of therapeutical effect is practically determined by the duration of the active ingredient per se.
  • the neuroprotective pharmaceutical compositions of the present invention can also be prepared in sustained release form, wherein the duration of the therapeutical effect is affected by the form of the composition too (pharmaceutical compositions of regulated, sustained or delayed active ingredient delivery).
  • compositions of the present invention can be prepared by conventional methods of pharmaceutical industry.
  • the tablets and capsules can contain lactose (monohydrate, anhydrate, powdered, dried etc.) mannitol, cellulose type (powdered, microcrystalline etc.) as filler.
  • lactose monohydrate, anhydrate, powdered, dried etc.
  • cellulose type powdered, microcrystalline etc.
  • Gelatine, polyvinyl pyrrolidone (having different molecular weight), cellulose ether type (hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose etc.), hydrolyzed starch, vegetable gum (gum arabic, guar gum etc.) can be used in aqueous solution or in solution formed with aliphatic alcohols having 1-4 carbon atoms in mixture of said solvents as binder.
  • the disintegrant used can be starch (potato starch, maize starch, wheat starch etc.) or a so-called super disintegrant, e.g. carboxymethyl cellulose (commercial name Ac-di-sol), sodium carboxymethyl starch (commercial name Primojel, Ultraamilopektin, Explo-Tab), polyvinyl pyrrolidone (commercial name Poliplasdone) etc.
  • lubricant e.g. alkali stearates (such as magnesium stearate, calcium stearate), fatty acids (e.g.
  • stearic acids commercial name Precirol, Cutina H
  • paraffin oil silicon oil, silicon oil emergents (talc, silica etc.
  • talc silicon oil emergents
  • active ingredients and auxiliary agents can be prepared for use in the compressing and anticapsulating procedure by liquid or dry granulating process or filtered powder homogenization.
  • Regulated or sustained release solid pharmaceutical compositions can be prepared by known methods of pharmaceutical industry.
  • Such compositions may be tablets containing various retardizing components [e.g. hydrophilic polymers, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyacrylic derivatives, polysaccharoses (e.g. guar gum, xanthan gum) etc. and mixtures thereof] or hydrophobic polymers (e.g. ethyl cellulose, methacrylic ester copolymers, polyvinyl acetate, polyvinyl butyral etc.) and mixtures thereof.
  • various retardizing components e.g. hydrophilic polymers, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyacrylic derivatives, polysaccharoses (e.g. guar gum, xanthan gum) etc. and mixtures thereof
  • hydrophobic polymers e.g. ethyl cellulose,
  • the retardizing effect is achieved by using a matrix which comprises a mixture of hydrophilic and hydrophobic polymers, or a mixture of polymers and fatty substances.
  • the tablets can also be prepared in multilayer forms wherein the active ingredients are incorporated into separate layers and thus the dissolution profile of the active ingredient can be better adjusted to the specific pharmacokinetical characteristics thereof.
  • the sustained release neuroprotective pharmaceutical compositions of the present invention can also be prepared in the form of coated pellets.
  • the preparation of the pellets can be performed separately from the active ingredient or from a mixture of the active ingredient.
  • the preparation of the pellets can be performed by extrusion or by spheronification rotogranulating methods or by coating the layers on placebo pellets.
  • a coating of the pellets can be carried out in rotating fluidizing equipment.
  • coating agent solutions or dispersents of water insoluble polymers formed with organic solvents preferably aliphatic alcohols containing 1-3 carbon atoms and/or chlorinated hydrocarbons containing 1-2 carbon atoms and/or acetone and/or ethylacetate or mixtures thereof
  • organic solvents preferably aliphatic alcohols containing 1-3 carbon atoms and/or chlorinated hydrocarbons containing 1-2 carbon atoms and/or acetone and/or ethylacetate or mixtures thereof
  • the neuroprotective pharmaceutical compositions according to the present invention can also be prepared and used in the form of osmotic or diffusion-osmotic compositions.
  • Tablets containing the active ingredient and hydrophilic polymers e.g. hydroxypropyl methyl cellulose
  • hydrophilic polymers e.g. hydroxypropyl methyl cellulose
  • a film-layer either semipermeable (e.g. cellulose acetate) or permeable (e.g. amino methacrylate copolymer) for the active ingredient, thereafter an orifice is formed in said layer, through which the active ingredient is optically pushed out into the aqueous medium.
  • the compounds of the general Formula and pharmaceutically acceptable acid addition salts thereof can be used particularly for the reduction of the consequences of acute ischemic or traumatic brain and spinal damage, especially in the various types of stroke or cerebral vasospasm, severe brain vessel occlusion, neuronal loss and its functional consequences in the case of head and spinal injuries caused by accidents; or for the treatment of neurodegenerative disorders; or for the treatment of motoneuron disease (ALS), sclerosis multiplex or Creutzfeld- Jakob disease; or for the prevention of stroke; whereby preventive treatment can be started after the event of first stroke.
  • ALS motoneuron disease
  • sclerosis multiplex or Creutzfeld- Jakob disease
  • a neuroprotective method of treatment which comprises administering to the patient in need of such treatment a pharmaceutically acceptable amount of a compound of the general Formula I or a pharmaceutically acceptable salt thereof, preferably (lR,2S,4R)-(-)-2-(2-dimethylaminoethoxy)-2- ⁇ henyl- l,7,7-trimethyl-bicyclo[2.2.1]heptane of the Formula II or a pharmaceutically acceptable acid addition salt thereof.
  • the neuroprotective effect of deramciclane was demonstrated in a model of global cerebral ischemia induced by bilateral carotid occlusion.
  • male Mongolian gerbils weighing 50-80 g were used.
  • Deramciclane was administered at 3x30 mg/kg intraperitoneally 60 min before, 30 and 90 min after surgery.
  • Deramciclane was suspended in 0.4 % methyl-cellulose solution.
  • the right and left common carotid arteries were exposed through an anterior midline cervical incision and isolated from the vagus nerves and the surrounding tissues.
  • Full arrest of carotid blood flow was achieved by tightening an aneurysm clip for 3 min.
  • the body temperature of the animals was kept at the individual preoperative level (37.5 ⁇ 0.5 °C) with the help of a heating pad and a heating lamp.
  • the animal performed an arm entry when it entered the arm and proceeded at least the distance of its body length.
  • the gerbil was considered to exit the arm when it left it fully.
  • Differences between groups were statistically evaluated by Kruskal-Wallis ANOVA. In case of p ⁇ 0.05 significance Mann- hitney U-test was used for paired comparisons.
  • the animals were anesthetized with 60 mg/kg i.p. pentobarbital (10 ml/kg) and perfused through the heart first with saline then with a fixative solution containing 0.1 % glutaraldehyde, 4 % paraformaldehyde, and 0.2 % picric acid in 0.1 M phosphate buffer pH 7.4 for 30 min.
  • the brain was removed from the skull and post-fixed for at least 1 week at 4 °C in the same fixative solution.
  • deramciclane in the applied dose significantly reduced the proportion of cell death in the hippocampal CAl region and decreased the locomotor activity of animals into the normal range in parallel to the improvement of histological score.
  • Deramciclane was not only protective against neuronal cell death but it was also effective in normalizing the clinically important behavioural anomalies.
  • deramciclane protected against neuronal loss induced by global cerebral ischemia as well as against behavioural anomalies developed in consequence of neuronal death.
  • This surprising effect of deramciclane was not possible to be predicted because ritanserin, which also had a 5-HT 2A/2 c mode of action and anxiolitic effect in animal experiments, did not produce neuroprotective effect in this model.
  • deramciclane possessed neuroprotective activity because the compound considerably reduced neuronal cell death in the CAl region of the hippocampus as well as reduced hyperactivity, which was the consequence of neuronal death observed four days after global cerebral ischemia caused by bilateral common carotid artery occlusion in Mongolian gerbils.
  • the therapeutic application of deramciclane can be favourable for the treatment of acute ischemic or traumatic brain and spinal cord damages e.g.
  • Tablets having the following composition are prepared by known methods of pharmaceutical industry:
  • Gelatine capsules having the following composition are prepared by known methods of pharmaceutical industry:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Urology & Nephrology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Furan Compounds (AREA)

Abstract

L'invention concerne l'utilisation de composés de formule générale (I), dans laquelle R3 représente l'hydrogène ou hydroxy, R1 représente l'hydrogène ou alkyle, et R2 représente alkyle, ainsi que l'utilisation de sels d'addition acides acceptables pharmaceutiquement dans le cadre de la préparation de compositions pharmaceutiques possédant un effet neuroprotecteur.
PCT/HU2004/000062 2003-06-23 2004-06-22 Utilisation de derives de bicyclo[2.2.1]heptane pour la preparation de compositions pharmaceutiques neuroprotectrices Ceased WO2004112769A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
BRPI0411772-7A BRPI0411772A (pt) 2003-06-23 2004-06-22 uso de derivados de biciclo[2.2.1]heptano para o preparo de composições farmacêuticas neuroprotetoras
US10/562,393 US20060258750A1 (en) 2003-06-23 2004-06-22 Use of bicyclo[2.2.1]heptane derivatives for the preparation of neuroprotective pharmaceutical compositions
AU2004248982A AU2004248982A1 (en) 2003-06-23 2004-06-22 Use of bicyclo[2.2.1]heptane derivatives for the preparation of neuroprotective pharmaceutical compositions
JP2006516495A JP2007516165A (ja) 2003-06-23 2004-06-22 神経防護作用医薬組成物の製造におけるビシクロ［２．２．１］ヘプタン誘導体の使用
CA002529254A CA2529254A1 (fr) 2003-06-23 2004-06-22 Utilisation de derives de bicyclo[2.2.1]heptane pour la preparation de compositions pharmaceutiques neuroprotectrices
SK5008-2006A SK50082006A3 (sk) 2003-06-23 2004-06-22 Použitie bicyklo[2.2.1]heptánových derivátov na prípravu neuroprotektívnych farmaceutických kompozícií
YUP-2005/0954A RS20050954A (sr) 2003-06-23 2004-06-22 Upotreba derivata biciklo/2.2.1/heptana za pripremanje neurozaštitnih farmaceutskih preparata
MXPA05014127A MXPA05014127A (es) 2003-06-23 2004-06-22 Uso de derivados de biciclo[2.2.1]heptano para la preparacion de composiciones farmaceuticas neuroprotectoras.
EA200600022A EA010868B1 (ru) 2003-06-23 2004-06-22 Применение производных бицикло[2.2.1]гептана для приготовления нейропротекторных фармацевтических композиций
HR20060023A HRP20060023A2 (en) 2003-06-23 2004-06-22 Use of bicyclo[2.2.1]heptane derivatives for the preparation of neuroprotective pharmaceutical compositions
UAA200600574A UA81052C2 (en) 2003-06-23 2004-06-22 Use of bicyclo [2.2.1] heptane derivatives for the preparation of neuroprotective pharmaceutical compositions for the reduction of the consequences of ischemic or traumatic brain and spinal damage
EP04743721A EP1660063A1 (fr) 2003-06-23 2004-06-22 Utilisation de derives de bicyclo [2.2.1]heptane pour la preparation de compositions pharmaceutiques neuroprotectrices
IL172408A IL172408A0 (en) 2003-06-23 2005-12-06 Use of bicyclo[2.2.1] heptane derivatives for the preparation of neuroprotective pharmaceutical compositions
IS8239A IS8239A (is) 2003-06-23 2006-01-18 Notkun tvíhring[2.2.1] heptanafleiða til að framleiða taugaverndandi lyfjablöndur
NO20060277A NO20060277L (no) 2003-06-23 2006-01-19 Anvendelse av bisyklo [2.2.1] heptanderivater til fremstilling av nevrobeskyttende farmasoytiske sammensetninger

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU0301906A HUP0301906A3 (en) 2003-06-23 2003-06-23 Use of bicyclo[2.2.1]heptane derivatives for producing of pharmaceutical compositions having neuroprotectiv activity
HUP0301906 2003-06-23

Publications (1)

Publication Number Publication Date
WO2004112769A1 true WO2004112769A1 (fr) 2004-12-29

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PCT/HU2004/000062 Ceased WO2004112769A1 (fr) 2003-06-23 2004-06-22 Utilisation de derives de bicyclo[2.2.1]heptane pour la preparation de compositions pharmaceutiques neuroprotectrices

Country Status (23)

Country Link
US (1) US20060258750A1 (fr)
EP (1) EP1660063A1 (fr)
JP (1) JP2007516165A (fr)
KR (1) KR20060023997A (fr)
CN (1) CN1812778A (fr)
AU (1) AU2004248982A1 (fr)
BG (1) BG109414A (fr)
BR (1) BRPI0411772A (fr)
CA (1) CA2529254A1 (fr)
CZ (1) CZ200631A3 (fr)
EA (1) EA010868B1 (fr)
HR (1) HRP20060023A2 (fr)
HU (1) HUP0301906A3 (fr)
IL (1) IL172408A0 (fr)
IS (1) IS8239A (fr)
MX (1) MXPA05014127A (fr)
NO (1) NO20060277L (fr)
PL (1) PL378630A1 (fr)
RS (1) RS20050954A (fr)
SK (1) SK50082006A3 (fr)
UA (1) UA81052C2 (fr)
WO (1) WO2004112769A1 (fr)
ZA (1) ZA200510138B (fr)

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WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP2248524A2 (fr) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Agents préventifs/remèdes pour l'incontinence de stress et procédé de séléction de ceux-ci
WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
WO2019131902A1 (fr) 2017-12-27 2019-07-04 武田薬品工業株式会社 Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale

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CZ301168B6 (cs) * 2008-10-09 2009-11-25 Ústav chemických procesu Akademie ved Ceské republiky Zpusob a zarízení pro izolaci kyseliny tereftalové
US11478467B2 (en) 2017-05-04 2022-10-25 Sreenivasarao Vepachedu Targeted drug rescue with novel compositions, combinations, and methods thereof

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WO2003007926A2 (fr) * 2001-07-18 2003-01-30 EGIS Gyógyszergyár Rt. Composition pharmaceutique pour le traitement du declin et/ou des atteintes des fonctions cognitives

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Cited By (9)

* Cited by examiner, † Cited by third party
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EP2248524A2 (fr) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Agents préventifs/remèdes pour l'incontinence de stress et procédé de séléction de ceux-ci
EP2400300A1 (fr) 2004-08-25 2011-12-28 Takeda Pharmaceutical Company Limited Procédé de sélection d'agents préventifs/remèdes pour l'incontinence de stress
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
EP2727585A1 (fr) 2006-05-16 2014-05-07 Takeda Pharmaceutical Company Limited Méthode de dépistage in-vivo
EP2742936A1 (fr) 2006-05-16 2014-06-18 Takeda Pharmaceutical Company Limited Composé hétérocyclique condensé et son utilisation
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP2789338A2 (fr) 2007-11-15 2014-10-15 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
WO2019131902A1 (fr) 2017-12-27 2019-07-04 武田薬品工業株式会社 Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale

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SK50082006A3 (sk) 2006-05-04
CZ200631A3 (cs) 2006-05-17
HUP0301906A2 (en) 2006-02-28
IS8239A (is) 2006-01-18
KR20060023997A (ko) 2006-03-15
HRP20060023A2 (en) 2006-05-31
UA81052C2 (en) 2007-11-26
BG109414A (bg) 2006-11-30
HUP0301906D0 (en) 2003-08-28
EA010868B1 (ru) 2008-12-30
PL378630A1 (pl) 2006-05-15
BRPI0411772A (pt) 2006-08-08
ZA200510138B (en) 2007-03-28
CN1812778A (zh) 2006-08-02
JP2007516165A (ja) 2007-06-21
HUP0301906A3 (en) 2006-03-28
EP1660063A1 (fr) 2006-05-31
AU2004248982A1 (en) 2004-12-29
MXPA05014127A (es) 2006-02-24
EA200600022A1 (ru) 2006-08-25
CA2529254A1 (fr) 2004-12-29
RS20050954A (sr) 2007-08-03
US20060258750A1 (en) 2006-11-16
IL172408A0 (en) 2006-04-10

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